Gliomas are tumors derived from glia or their precursors within the central nervous system. Malignant gliomas, the most common subtype of primary brain tumors, are aggressive, highly invasive and neurologically destructive. Clinically, gliomas are divided into four grades and the most aggressive of these, grade IV astrocytoma or glioblastoma multiforme (GBM), is also the most common in humans (Kleihues 2000; Maher et al. 2001). Despite maximum treatment efforts, median survival of patients diagnosed with GBM ranges from 9 to 12 months, a statistic that has changed very little in decades. Primary brain tumors, like all cancers, share a relatively restricted set of characteristics crucial to their phenotype: proliferation in the absence of external growth stimuli, avoidance of apoptosis and no limits to replication, escape from both external growth-suppressive forces and the immune response, formation of new blood vessels and the ability to invade normal tissues (Hanahan and Weinberg 2000). Furthermore, despite their striking heterogeneity, common alterations in specific cellular signal transduction pathways occur within most GBMs. Deregulation of signal transduction, which accounts for aberrant responses to distinct soluble factors, is also a common feature of these tumors, and modulation of signaling pathways has become an option for targeted therapies (Sebolt-Leopold and Herrera 2004).
Previous work from our group (Zanata et al. 2002) identified the co-chaperone stress-inducible phosphoprotein 1 (STI1) as a cell-surface ligand for the membrane glycosylphosphatidylinositol (GPI) anchored cellular prion (PrPC), which leads to the activation of several signal transduction pathways, some of which modulate cell survival. Stress-inducible phosphoprotein 1 (STI1), also referred to, in the case of the human homologue, as Hop (Hsp70/Hsp90 organizing protein), is a 66 kDa protein first identified in yeast and originally described as a co-chaperone that binds to both Hsp70 and Hsp90, and regulates their activities (Chen and Smith 1998; Nicolet and Craig 1989; Song and Masison 2005). Due to the 98% sequence homology between the mouse (STI1) and human (Hop) molecules (Table 1), the term STI1/Hop will be used throughout this disclosure as the designation for the protein. In cases where the intention is to specify either the mouse or human homologue, the respective designation STI1 or Hop alone will be made.
STI1/Hop is present in diverse cellular locations, exists within nuclear transcription complexes, is able to move dynamically between the cytoplasm and the nucleus (Odunuga et al. 2004) and although it lacks a transmembrane domain or a signal peptide for membrane transport, it is also present at the cell surface (Martins et al. 1997; Zanata et al. 2002). In fact, many proteins expected to be confined in the cytoplasm are also at the cell surface where they play specific functions, in particular as receptors for plasma proteins (Nickel 2005). Previous work had already showed that STI1/Hop involvement in Hsp90-independent complexes relates to diverse cellular events such as transcription, protein folding and translocation, viral replication, signal transduction and cell division (Odunuga et al. 2004). STI1/Hop was shown to be secreted by normal astrocytes (Lima et al. 2007) and by HT-1080 fibrosarcoma cells together with other chaperones and co-chaperones, suggesting that these proteins may form extracellular active Hsp90 complexes related to MMP2 (metalloproteinase 2) activation and consequent tumor invasiveness (Eustace and Jay 2004; Eustace et al. 2004). Another study also related the activity of Hsp90, an STI1/Hop partner, to a molecular mechanism of tumor response selectivity to geldanamycin (Kamal et al. 2003).
Previous work from our group showed that a cellular prion-binding peptide designed on the basis of the complementary hydropathy theory (Boquet et al. 1995; Brentani 1988; Martins et al. 1997), later identified as a domain of STI1/Hop (Zanata et al. 2002), was able to activate the PKA and Erk signaling pathways, with the former being associated with cell survival in retinal explants (Chiarini et al. 2002). In addition, recombinant STI1/Hop was reported to modulate retinal proliferation and cell death (Arruda-Carvalho et al. 2007), to trigger neuroprotection and neuritogenesis in hippocampal neurons through PKA and MAPK pathways, respectively (Lopes et al. 2005) and to induce endocytosis-dependent MAPK signaling (Americo et al. 2007; Caetano et al. 2008).